APPLICANT'S DESCRIPTION: (Provided by Applicant) The ultimate goal of this project is to improve the treatment of dysplastic Barrett's esophagus (BE) by optimizing photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA). The incidence of esophageal adenocarcinoma is rising faster than any other cancer and BE is the primary risk factor for developing this malignancy. PDT has become a commonly used method for eradication of BE with minimal morbidity. ALA is an attractive photosensitizer (PS) for PDT because it can be given orally just prior to illumination and has minimal side effects. However, ALA has not gained widespread acceptance because of its poor ablation efficiency relative to other photodynamic agents. This proposal describes studies modulating various ALA-PDT treatment parameters with the goal of improving PDT efficiency. There are three specific aims: (1) enhance ALA-PDT using differentiation therapy, (2) enhance ALA-PDT by modifying light delivery and (3) develop short-term surrogate endpoints that predict the long-term clinical outcome of ALA-PDT. These aims will be accomplished by performing a single prospective, randomized clinical trial in patients with BE and high-grade dysplasia (HGD) or T1N0M0 esophageal cancer. Cell differentiation is known to increase the production of protoporphyrin IX (PPIX) which is the PS induced by ALA and retinoids are differentiating agents capable of redirecting cells to their normal phenotypic maturation. The ability of 13-cis retinoid acid to induce differentiation and improve ALA-PDT will be determined during this trial. In addition to examining the effect of 13-cis retinoid acid on clinical outcome, the effect of 13-cis retinoid acid on the enzymes involved in the generation of PPIX will be analyzed. In a separate arm of the trial the hypotheses that lower light fluence rates and fractionation of light dose enhance the clinical efficacy of ALA-PDT will be tested. In the third specific aim, an in vivo dosimeter will be developed that will enable spectroscopic measurements to be taken during PDT. These measurements will be used to identify parameters that predict the clinical outcome of PDT. These studies will significantly advance our understanding of ALA-PDT, enhance its clinical use for the treatment of dysplastic BE and are likely to be applicable to PDT of other diseases.